The induction of
cellular senescence is often seen a beneficial therapeutic strategy for
preventing the growth of cancer. This
may certainly be the case in the short-term, but the biological impact of
senescent cells in the long-term is greatly understudied. Senescent cells are more than just a
permanent state of growth arrest; they also display an immune-evoking pro-inflammatory
secretory phenotype. However, for some
yet unknown reason, senescent cells can evade immune clearance and potentially
alter their microenvironment by continuously secreting of pro-inflammatory
factors. These pro-inflammatory factors
are thus one possible mechanism by which senescent cells could promote the
reoccurrence of cancer following senescence therapy.

Prostate
cancer (PCa) is one of the most common cancers in American men and a leading
cause of cancer- related death. Initial
PCa tumours are dependent upon the presence of androgen, such as testosterone,
for growth. As such, undergoing androgen
deprivation therapy (ADT) is currently the most effective procedure for suppressing
tumour progression. ADT not only causes tumour cell death leading to reduction
in tumour size, but also induces a proliferative arrest in a large fraction of
tumour cells. Within a few years
following ADT, the PCa can reemerge, that are no longer dependent on androgen
for growth, and for which there are currently no effective therapeutic
treatment strategies. Recurrence of nonresponsive or androgen-refractory
tumours reduces patient life expectancy to less than two years.

To
investigate the mechanisms of PCa reoccurrence, Burton et al focused their
efforts on the cells undergoing proliferative arrest in response to ADT. They provide evidence that androgen
deprivation-induced proliferative arrest is in fact cellular senescence, termed
ADIS (androgen deprivation-induced senescence).
The induction of ADIS appears to be due to intracellular up-regulation
of ROS and consequently DNA damage. Their data show that continuous exposure of
an androgen-sensitive PCa cell line (LNCaP) to the senescent microenvironment,
leads to the appearance of cells with androgen-independent characteristics. Further, it is shown that pharmacologic
enforcement of the p53-Bax pro-death pathway prior to androgen deprivation (AD)
preferentially triggers cellular death rather than cellular senescence. It is
thus postulated that the use of drug therapies prior/during ADT that promote
cell death rather than cellular senescence may prevent/reduce androgen
refractory PCa.

The more difficult
question to answer concerns the mechanisms that facilitate the appearance of cells
with androgen-refractory characteristics. One possibility is that the secretory
phenotype of senescent cells stimulates the proliferation of so called, cancer
stem cells (CSCs). The senescent
secretory profile is similar to that which occurs during a wound healing
response, suggesting CSC may proliferate to facilitate wound repair but in this
context facilitates tumour formation. Interestingly,
TAp63, a marker of basal prostatic cells, a progenitor population known to
survive androgen ablation and is involved in the maintenance of adult stem
cells is elevated in the emerging androgen-refractory cells. TAp63
overexpression has also been associated with resistance to premature senescence,
suggesting the emerging androgen-refractory cells, at least in part, may be the
result of selective pressure favoring the proliferation of cells resistant to
ADIS. Further, the secretory phenotype
of the surrounding senescent cells may facilitate the expansion of ADIS
resistant cells.

This work is important because it addresses the controversial issue
of whether AD-induced senescence in cancer cells promotes the progression of
the disease; if this is the case, these phenomena can provide therapeutic
targets to prevent progression. Additionally,
this study provides a method for generating and expanding androgen-refractory
cells in a shorter period of time, cells which can be used for further
study.

Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer1. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer1, 3, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP)4, 5has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage6. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs)7, which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer8 or depleted of senescent HSCs, indicating that the DCA–SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis3, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.

Different anatomic and physiological changes occur in the lung of aging people that can affect pulmonary functions and different pulmonary diseases heterogeneously, including deadly diseases such as chronic obstructive pulmonary disease (COPD)/emphysema and idiopathic pulmonary fibrosis (IPF), and can be related to an acceleration of the aging process. The individual genetic background, as well as the exposure to a variety of toxic substances (cigarette smoke in primis) can contribute significantly to accelerating pulmonary senescence. Premature aging can impair lung function by different ways: by interfering specifically with tissue repair mechanisms after damage, thus perturbing the correct crosstalk between mesenchymal and epithelial components; by inducing systemic and/or local alteration of the immune system, thus impairing the complex mechanisms of lung defense against infections; and by stimulating a local and/or systemic inflammatory condition (inflammaging). According to recently proposed pathogenic models in COPD and IPF, premature cellular senescence likely affects distinct progenitors cells, leading to stem cell exhaustion. Mesenchymal stem cells in COPD, alveolar epithelial precursors in IPF. In this review, the large amount of data supporting this pathogenic view are discussed, with emphasis on the possible molecular and cellular mechanisms leading to the severe parenchymal remodeling that characterizes, in different ways, these deadly diseases.

Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS) affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.

ABSTRACT

Cellular senescence, an irreversible cell cycle arrest induced by a diversity of stimuli, has been considered as an innate tumor suppressing mechanism with implications and applications in cancer therapy. Using a targeted proteomics approach we show that fibroblasts induced into senescence by expression of oncogenic Ras exhibit a decrease of global acetylation on all core histones, consistent with formation of senescence-associated heterochromatic foci. We also detected clear increases in repressive markers (e.g., >50% elevation of H3K27me2/3) along with decreases in histone marks associated with increased transcriptional expression/elongation (e.g., H3K36me2/3). Despite the increases in repressive marks of chromatin, 179 loci (of 2206 total) were found to be upregulated by global quantitative proteomics. The changes in the cytosolic proteome indicated an upregulation of mitochondrial proteins and downregulation of proteins involved in glycolysis. These alterations in primary metabolism are opposite of the well-known Warburg effect observed in cancer cells. This study significantly improves our understanding of stress-induced senescence and provides a potential application for triggering it in anti-proliferative strategies that target the primary metabolism in cancer cells.

ABSTRACT

Therapy-induced senescence (TIS) as a permanent growth arrest can be induced by various stimuli, including anticancer compounds. TIS has emerged as a promising strategy to overcome resistance phenomena. However, senescent cancer cells might regain proliferation activity in vivo or even secrete tumor-promoting cytokines. Therefore, successful exploitation of TIS in cancer treatment simultaneously requires the development of effective strategies to eliminate senescent cancer cells. Virotherapy aims to selectively hit tumor cells, thus a combination with senescence-inducing drugs was explored. As a model we chose measles vaccine virus (MeV), which does not interfere with cellular senescence by itself. In different tumor cell types, such as hepatoma, pancreatic and mammary gland carcinoma, we demonstrate efficient viral replication and lysis after TIS by gemcitabine, doxorubicin or taxol. Applying real time imaging, we even found an accelerated lysis of senescent cancer cells, supporting an enhanced viral replication with an increase in cell-associated and released infectious MeV particles. In summary, we show as a proof-of-concept that senescent tumor cells can be efficiently exploited as virus host cells by oncolytic MeV. These observations open up a new field for preclinical and clinical research to further investigate TIS and oncolytic viruses as an attractive combinatorial future treatment approach.

Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15INK4b and p21CIP1. Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.

Persistent activation of the DNA-damage
response (DDR) can trigger cells to undergo cellular senescence, a state of
irreversible, immune evoking, growth arrest.
In such a way, cellular senescence can prevent tumourigenesis firstly by
blocking cells from replicating and producing abnormal and potentially
cancerous daughter cells and secondly by coordinating their removal by immune
cells. Additionally, senescent cells can
aid tissue repair by preventing extensive cellular proliferation leading to
fibrosis, possibly triggered by replication stressed-induced DNA damage. However, if this orchestrated removal of
senescent cells becomes dysregulated, then persistent senescent cells can
promote tumourigenesis and tissue damage.

An aspect of the DDR in senescent cells is
the induction of an array of secretory factors, including
cytokines/chemokine’s, which are important in attracting/activating immune
cells to their vicinity. When immune
cells reach the locality of senescent cells, they can then specifically
recognize them by the expression of immune ligands on the cell membrane, a
process that may also be regulated primarily by the DDR. The specific ligands recognized and the
mechanism of senescent cell death will then be dependent upon the type of
immune cell interacting with the senescent cell.

However, cells induced to undergo permanent
growth arrest in vitro by the overexpression
of the cyclin dependent kinase inhibitor p16ink4a, do not develop an immune evoking
secretory phenotype until the addition of DNA damage. If cells in physiological or pathological
conditions can indeed undergo permanent cell cycle arrest in a p16 dependent,
DDR-independent manner, then these cells are unlikely to evoke an immune
response for their clearance. In support
of this, a recent study demonstrated that cells overexpressing p14(ARF) in the
epidermis of mice remained present for weeks after transgene silencing (Tokarsky-Amiel
et al 2013). Even if p16-induced
senescent cells do not display a pro-inflammatory phenotype, they can still
cause physiological problems simply by their inability to proliferate, an
essential feature required for tissue regeneration and maintenance. In this regard, the growth arrest and
pro-inflammatory phenotype of senescent cells can be investigated separately to
determine which feature is important in different physiological contexts.

Until the phenotype of p16-induced senescent
cells in vivo have been researched
more extensively, cellular senescence could be divided into two
separate types. Firstly, immunogenic senescence
related to a DNA damage response, consisting of a pro-inflammatory
phenotype and the presence of immune ligands, triggered by telomere shortening,
oncogene-activation, and chemical stressors.
Secondly, sterile senescence which lacks a pro-inflammatory
phenotype and the inability to evoke an immune response.

If this distinction is made, then studies
focused on the effect of cellular senescence on ageing, disease and cancer
development can better design their experiments and avoid confusion between
conflicting results due to differences in the types of senescence used.